Multiple Sclerosis (MS) is an important neurological disease. An immunomodulatory clinical trial was funded by the National Multiple Sclerosis Society (NMSS) to test the efficacy of Helminth-induced Immunomodulatory Therapy (HINT) in patients with relapsing remitting multiple sclerosis (RRMS). Helminth-therapy, using T. suis ova (TSO), has been successfully applied in phase II clinical trials for Crohn's disease and autoimmune colitis. We have assembled an interdisciplinary research team of basic researchers and clinicians, and completed preliminary studies to evaluate the safety of TSO treatment for RRMS. These clinical trials showed promise in establishing the efficacy and safety of using TSO in humans, but did not reveal the mechanism of the immunoregulatory effect. The long-term objective of this proposal is to utilize samples from subjects of the parent HINT clinical trial to identify immunological markers that correlate with the specific effects of the therapy in order to understand the mechanisms of immunomodulatory intervention in RRMS. The hypothesis to be tested is that HINT will beneficially modify the clinical outcome of RRMS by (1) inducing anti-helminth immunity and reshaping the pro-inflammatory systemic environment in parallel with the activation of anti- inflammatory Th2 cells (Specific Aim 1), (2) increasing the level of regulatory cells and mediators in the peripheral circulation (Specific Aim 2), and (3) decreasing inflammation in the central nervous system (CNS) by redirecting the traffic of pro-inflammatory cells to the anti-inflammatory regulatory site in the gut (Specific Aim 3). HINT may offer an innovative, unique, safe, and efficacious alternative for RRMS disease management. To understand the immunoregulatory mechanisms of TSO treatment would lead to the expansion of this approach into a broad range of autoimmune diseases. PUBLIC HEALTH RELEVANCE (provided by applicant): Multiple sclerosis (MS) is the most common disabling, non-traumatic neurological disease among young adults. MS typically presents with recurrent attacks of neurological dysfunction, known as the relapsing-remitting form of MS (RRMS). Among the hypotheses advanced to explain MS is the hygiene hypothesis, which posits that a lack of evolutionary normal infectious exposures during childhood predisposes a person to exaggerated immune responses in adulthood, possibly leading to atopy and autoimmune diseases such as MS. Based on the hygiene hypothesis, probiotic therapy, which uses helminths as the probiotic agent, was proposed as a potential treatment of RRMS. The National Multiple Sclerosis Society (NMSS) has funded an immunomodulatory clinical trial to test the efficacy of Helminth-induced Immunomodulatory Therapy (HINT) in patients with relapsing remitting multiple sclerosis (RRMS). We will utilize samples from subjects of the parent HINT clinical trial to identify immunological markers that correlate with the specific effects of this therapy. This knowledge will lead to a better understanding of the mechanisms of HINT immunomodulatory intervention in RRMS, and open up the possibility of expanding this approach to other autoimmune diseases.